Professional Documents
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Sop e Microbiota
Sop e Microbiota
Resum:
REVIEW
Food Torribera Campus, Pharmacy and Food Sciences Faculty, University of Barcelona,
Santa Coloma de Gramanet, Spain
• Mechanisms involving the gut microbiota may be a potential pathogenic factor in the
development of PCOS.
• Microbiota composition in PCOS patients differs from healthy controls.
• Studies suggest that obesity, IR and hormonal imbalance could lead to dysbiosis.
• Modulation of the gut microbiome through diet as a potential PCOS treatment.
1
Introduction
when the Rotterdam Consensus criteria are used (1). The syndrome, defined by these
criteria, is characterised by the presence of at least two of the three classical features of
that IR and inflammation are responsible for the increased risk of diabetes, metabolic
syndrome and cardiovascular disease observed in long term PCOS patients (2).
The ethology of PCOS remains unclear, although studies indicate that both genetic
and environmental factors contribute to the syndrome (3). In anterior years, reviews had
It is known that a big diversity exists in the clinical presentation of PCOS, because
not all women diagnosed with it have the same pathological phenotypes (3). PCOS
phenotypes vary with ethnicity, weight, age and region (5). Even though, the most
excluded before treating it. Nowadays, due to the prevalence of this syndrome, alternative
treatments are gaining much interest among population. It is for this reason that scientific
2
evidence is focusing a lot on the relationship between PCOS and a possible dysbiosis as
In order to write this bibliographic review a systemic search of different concepts has
been performed in PubMed and Scopus databases. Keywords used to filter through the
databases were: PCOS AND (“gut microbiota” OR microbiome OR dysbiosis). For this
review, the articles included were those that reported the alterations of the intestinal
microbiota under PCOS condition. Additionally, specific terms were used in the search
of information regarding to hepatic steatosis (PCOS AND NAFLD) and the urinary
metabolites (PCOS AND urinary AND metabolites). Regarding the information related
to dietary treatment, different articles were searched directly from "Nutrients" website.
Selection criteria for all articles was restricted to a 10-year window, even though most of
the selected ones have been published in recent 4 years. Furthermore, studies without
humans as subjects were excluded. Finally, in order to obtain a higher level of scientific
evidence, the primary selected sources were meta-analyses, reviews and systematic
reviews; even so, there are as well some clinical research articles.
Results
Overall, a summary of 24 articles were included, as specifying into the different topics, a
total of 37 articles and an online website were added later. Based on the first information
obtained from the abstracts of the articles, a script was made. The following includes the
3
1. The human microbiota
The microbiota is the set of microorganisms that colonize the epidermal surface and
the mucous membranes. Throughout the body, humans have a colonizable total of 400m.
The microbiota is changing with life, as we grow, we create our microbiota. In the
elderly, the gut microbiota become compositionally unstable and less diverse, events that
(6). The microbiota will change over a lifetime and there are many external factors that
will influence it. Endogenous and exogenous factors influence the gut microbiota:
4
It exists a symbiotic relationship between the bacteria that inhabit our intestines and
ourselves, since we provide them with a place to live and, in return, they help us in
thanks to the "barrier" effect that prevents the entry of bacteria, parasites and
foreign viruses.
• Nutrient metabolism: help digest food and absorb nutrients, providing extremely
Moreover, produce vitamins, such as B and K, which the human body is not
capable of synthesize.
During the past decade, science has heavily focussed on the microbiota and its broad
functions throughout the body. The link between the dysbiosis of gut microbiota and the
development of PCOS was initially studied in 2012 by Tremellen and Pearce. Afterwards,
many clinical studies confirmed that gut microbiome composition differs when
Gut dysbiosis, brought about a poor diet, creates an increase in gut mucosal
permeability, with a resultant decrease of protective bacteria and increase in the passage
5
of lipopolysaccharide from Gram negative colonic bacteria into the system circulation
(2).
play a crucial role in immunomodulation (8). One of the metabolites produced for these
gut microbes (bile acids) may contribute to the pathogenesis and development of diabetes
The intestinal microbiota is also able to regulate circulating estrogen levels (we refer
We actually know that not only women with PCOS have alterations of enteric
microorganisms, but also particular species are related to PCOS phenotypes (11).
There are different possible mechanisms through which gut microbes are associated
with PCOS. Referring to that, intestinal microbes influence the progression of PCOS by
metabolite production.
For instance, alterations of the gut microbiota and less microbial diversity led to (11):
with poor levels of IL-22, consequently, brown adipose tissue couldn’t help
6
improving PCOS symptoms. On the other hand, IL-22 might target ovarian
This low production of SCFAs increases the inflammation and insulin resistance
axis does not work the way it is supposed to due to the lack of YY peptide (PYY)
and ghrelin.
have higher levels of Provotella (related with androgen levels such as testosterone
excess.
Even the PCOS factors remains unclear, we already know that the pathogenesis of
PCOS not only depends on the genetic factors, but also on the epigenetics. Within the
disruptors have been proposed as an important factor in the develop of the syndrome, as
they have the ability to interfere with hormone sensitivity systems (12). Knowing that gut
microbiota is affected by sex hormones, it is worth bearing in mind that, even more
research is required, it could exist a forthright alteration in gut bacteria due to these
disruptors (13).
7
One of the most studied endocrine disruptors in relation to PCOS is tributyltin
(TBT) (14). TBT has a negative role in PCOS, as inhibits aromatase, an enzyme whose
function is to convert testosterone into estradiol. As a result, reducing the function of this
enzyme could increase testosterone, worsening the symptoms of PCOS. Other disruptors
Body weight could be influenced by the gut microbiota due to its complex effects
As said before, it is currently known that women with PCOS have an altered
microbiota, different from those without the disease. We can say that women with PCOS
without PCOS. Several bacterial taxa associated with PCOS status was also correlated
with metabolic biomarkers such as waist-to-hip ratio and triglycerides (TG) (16).
(control) patients, a relationship between PCOS and specific gut microbiota has been
found (1). An increase in several taxa at the genus levels, specifically the genus
8
It is important to point out that the taxa Parabacteroides distasonis was not only
elevated in PCOS obese women but also in lean women with PCOS. This shows us an
altered gut microbiota not only in overweight but also in lean women with this syndrome
(18).
resistance (IR). IR occurs when cells in the muscle, fat, and liver don’t respond well to
insulin and can’t easily take up glucose from the blood (extra glucose stays in the
bloodstream rather than entering the cells). As a result, pancreas makes more insulin to
help glucose enter to the cells. Over time, this plight could develop type 2 diabetes (T2D)
(19).
Gut microbiota dysbiosis is one of the factors that mediate the appearance of IR
(and even the subsequent obesity). It seems that IR led to metabolic sequelae such as
He F and Li Y (20) studied the relation between the gut microbial composition in
PCOS with IR. Comparing with PCOS without IR and healthy controls, a difference in
the microbial composition of PCOS with IR was found. It does exist a relative abundance
of Rothia and Enterococcus in this PCOS-IR patients, suggesting that the bacteria of the
gut microbiota could potentially play a key role in the pathogenesis of PCOS by
9
In this context, major risk factors for T2D such as overnutrition and low dietary
fibre involve the gut and have been found to be associated with increased IR, decreased
The leaky gut hypothesis also has to do with alterations of the insulin receptor
(16). This hypothesis relates to the permeability of the intestinal barrier, caused for a high
sugar/fat and low dietary fibre diet. As previously stated, this permeability will induce a
passage into the blood stream of toxins, antigens and bacteria; what finally leads to a
systemic inflammatory response. The insulin receptor will be altered for this chronic state
of inflammation, that affects multiple organs and follicular development. IR and the
Gut dysbiosis and its intestinal mucosal permeability not only increase the passage
of the mentioned inflammatory mediators, but also produces branch-chain amino acid
immune response of the body and reduce insulin sensitivity (22). A recent study found
that imidazole propionate (microbial metabolite produced from amino acid) was shown
to have higher concentrations in the portal and peripheral blood of patients with T2D (23).
This excess of insulin in PCOS play an elementary role in the already known
and adrenal gland, therefore, increasing levels of free testosterone by inhibiting the
synthesis of sex hormone binding globulin (SHBG) (25). To wit, PCOS with IR is a
10
metabolic problem that causes an alteration in the ovary too.
pathology seen as the first metabolic disorder in the referred ovary syndrome (26).
Fang-fang He and Yu-mei Li (22) write about the implication of the gut
seen that insulin is linked to the microbiota. Even though, other studies highlight the
interaction, through signal pathways and transduction, between IR and chronic subclinical
inflammation (28). Then, gut microbiota might be involved in the pathogenesis of PCOS
by mediating systemic low-grade inflammation and insulin resistance, also affecting the
ovulation disorders (22), a very representative clinical parameter in women with PCOS.
A recent study (29) had a deeper investigation in the correlation between gut
had hyperandrogenism. Among the findings, it stands out that the lower alfa-diversity of
the microbiome (seen as typical in PCOS) strongly correlated (negative correlation) with
hyperandrogenism, specifically with total testosterone level and hirsutism. It seems that
11
androgens may change the gut microbiome, worsening like this the progression and
pathology of PCOS.
We actually know that there is a permanent relationship between our gut and our
brain. The central nervous system has a constant bidirectional connection with the
digestive tract. It is for this reason that some people refer to our gut as our “second brain”.
An actual study (18) analysed the relationship between alterations in our intestinal
microbiota and the prevalence of gut–brain axis changes in PCOS. The study was
designed to test the possible involvement of the gut microbiota in metabolic disorders and
neurotransmitter production.
species present in the intestinal microbiota of women with PCOS when compared with
women without said diagnosis. The study reflected a possible microbial dysbiosis in
women with PCOS that could be associated with neuroendocrine changes, revealing a
were increased in PCOS against controls (18,30)). These bacteria might increase the level
12
of GABA, acting on the receptors of gonadotrophin-releasing hormone (GnRH) neurons
Thus far, the point of view has been lately focused on neuroendocrine impairments
associated with PCOS. This is because psychiatric disorders are more often diagnosed in
Eating disorders are one of the most common disorders among women with PCOS
(32). One of the links between PCOS and eating disorders refers to the elevated
testosterone concentrations, as these levels may promote food cravings, perhaps via a
cortisol) can increase insulin levels, leading to routes that can increase free circulating
testosterone (31).
Seems that the relationship between psychiatric disorders and PCOS will work in
both directions, the psychiatric disorders appear to function as cause and consequence.
13
If we take a deeper look, we can conclude that eating disorders can also modify
the gut microbiota, generally, leading to a reduction in diversity associated with poor
clinical outcomes (34). Régine P. M. Steegers-Theunissen et al. (31) postulate that the
psychological distress and its associated eating disorders during these periods lead to the
axis), which contributes to the development of PCOS and related comorbidities in these
We already know that women with PCOS have a specific microbiota, but it
appears that the microbiome is also important in the pathogenesis of the so-called non-
alcoholic fatty liver disease (NAFLD) (35). It is interesting to study the relationship
between PCOS and NAFLD, since its known that women with PCOS have a higher risk
At first, a higher prevalence of NAFLD has been observed in women with PCOS
with a body mass index (BMI) similar to women without PCOS (36). In the case of
adolescent girls with obesity, the prevalence rate ranged from 50% compared to 13% in
14
To delve into this topic, we will use the study carried out by Jobira B. et al (38),
in which 34 girls with similar parameters were equally divided into two groups: with and
without hepatic steatosis (HS). The results of said study were that those adolescents with
PCOS, obesity and HS had a dysbiosis of the microbiota compared to those with PCOS
and obesity but without HS. Then, a conclusion comes to light, since it seems that not
only PCOS and HS affect the microbiota separately, but also, if we add liver dysfunction
to the sum of PCOS and obesity, we can see other specific changes in the bacterial taxa
of the gut microbiota. Even so, the question remains about what the jumping-off point is
and if this relationship between PCOS and HS are causative or just associations.
The study by Del Chierico et al. (39) in pediatric population and the above-
mentioned study (38) agree about their findings in lower amounts of Bacteroidetes in
HS/NAFLD patients. Adolescent patients with HS were also found to have upregulation
of ethanol metabolism (39), and according to that, Jobira B et al. found a higher %RA
This suggests that bacteria taxa involved in ethanol production may contribute to
One of the pathogenic mechanisms between NAFLD and PCOS women has to do
with the accumulation of lipids in the liver (40). The high level of androgens, due to
gene transcription to prolong the half-life of very low-density lipoproteins (VLDL) and
15
Furthermore, as indicated previously, it is essential to note that IR can increase
the risk of NAFLD, since a higher prevalence of IR has been observed in women with
PCOS and NAFLD compared to women with the same endocrinopathy but without
steatosis (41).
Therefore, given the everyday higher prevalence of NAFLD in young women with
PCOS and the high risk of developing long-term liver complications, it would be a must
On the other hand, one of the factors influencing the development of NAFLD is
the increased dietary fructose (sugar especially found in fruit, honey, and processed foods
such as juices and other beverages (43)). This kind of diet led to an increase in the uptake
of fatty acids to the liver and a reduction in the fat transport of VLDL-triglycerides. As
patients) (44).
The scientific evidence available to date suggests that chronic and excessive
here], figure 3 describes the mechanisms of NAFLD development and the influence of
nutritional factors (44). So, in light of this, it could be crucial for patients with or at risk
16
2.6. Specific fecal and urinary metabolites
The study carried out by Ling Zhou et al (45) was the first in relate obese patients
diagnosed with PCOS with the use of fecal metabolomics combined with gut microbiota.
They compared obese patients with and without PCOS, finding a linear
relationship between gut microbiota, characteristic fecal metabolites and serum sex
hormones. PCOS obese patients have characteristic intestinal species that correlate with
and taurocholic acid. At the same time, a correlation was also revealed with serum sex
determined that fecal metabolites play a key role in the phenotypic changes caused by
hyperandrogenism.
women (41 diagnosed with PCOS and 66 healthy controls). The results of this study
showed a specific urinary steroid profile in PCOS patients. The urinary steroid profiling
markers for PCOS. Another function of the microbiota is to interpose in the metabolism
Between the latest findings associating PCOS and urinary metabolites we found
the work of Wei Zhou et al. (47). In this study, a variation of metabolic states was found
in different PCOS subtypes (healthy, with hyperandrogenism and with IR). A panel of 8
17
biomarkers was discovered from PCOS with hyperandrogenism vs IR: ribitol, trans-
inositol, oxalic acid and ribonic acid. The area under curve (AUC) for the metabolic
biomarkers was 0.8363. The AUC reached 0.9065 (with high sensitivity and specificity
All in all, it seems that the intestinal microbiota and its respective metabolites could
be used to diagnose PCOS (in a noninvasively way) and better clarify the pathological
science for knowing better about the ethology of PCOS. In connection with this, the study
warranted, and what is more, therapies could be more targeted for every phenotype and
Nowadays, the whole world is facing a pandemic, it is for this reason that severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most current topic. Some recent
studies have already point out not only the link and implications with gut microbiota, but
Wambier CG and Goren A (48) study and conclude that SARS-CoV-2 it is androgen
mediated. We come across the fact that the activity of the androgen receptor plays a
18
Following this path, the priming of the spike proteins by TMPRSS2 it is a basic required
step for potential infectivity of SARS-CoV-2. This could be one of the reasons why males
PCOS women had greater androgen receptor activity than non-PCOS, therefore, a
PCOS phenotype might worse the severity of the currently known SARS-CoV-2. Even
so, another risk factor for both the susceptibility to and the severity of the SARS-CoV-2
is obesity (and associated IR) (51). In this context, this is another PCOS feature that could
The pathogenesis of this disease is not fully understood, it is still a syndrome with an
exclusion diagnosis, for this reason, therapies are poorly targeted and possibly ineffective.
The actual chosen treatment after PCOS diagnostic is the use of oral contraceptives. Even
so, it is worth bearing in mind the undoubtedly growing interest about how to treat PCOS
with lifestyle changes. It is for this reason that PCOS patients are interested in a more
As it has already been mentioned, it exists a relation between dysbiosis and intestinal
inflammation, IR and all that this entails (hyperandrogenism, diabetes…). One of the
bases for the human health is the diet (total energy intake, macronutrient and
microbiota (52).
19
Now, what our field refers to, we will take into account the modulation of the gut
microbiome through diet as a potential PCOS treatment. Different studies show that it
can be very useful to control inflammation through the intake and / or supplementation
of:
• Omega-3: unsaturated fatty acid rich diets decrease the risk of insulin resistance
and its related complications; in this way, intake of omega-3 reduces the risk of
• Curcumin: this polyphenol may improve glycaemic control and lipid metabolism
property of curcumin may also play a role in glucose and lipid metabolisms and
the activity of cytochrome P450c17, and thereby reducing the synthesis of DHEA
(56).
20
• Green tea: it has been seen that this beverage with high amount of antioxidants
supporting like this the growth of beneficial microbial strains in PCOS women
(59).
mediators, including ghrelin and PYY, and regulating like this the levels of sex
barrier function of the gut and reduce the translocation of endotoxins across the
connection with this, Jamilian et al. (61) prove that co-administration of probiotic
resulted in decreased levels of testosterone and hirsutism and had also beneficial
21
• Myo-inositol: the effectivity of supplementation with 4g of myo-inositol/day on
function) (62).
By and large, improving all these parameters could result in an improved gut
leading to dysbiosis.
Instead of lifestyle interventions (diet, physical activity, good sleeping habits, stress
management…), the treatment of PCOS has been approached from many different
alternative therapies.
Regarding alternative treatments, another therapy for treating gut dysbiosis in PCOS
is the fecal microbial transplant (FMT) from healthy donors or representative microbes
from a healthy gut to re-diversify the gut microbiome. Despite the fact that there are
limited studies to support this idea, experimental studies show promise that adjusting the
gut microbial community in PCOS patient through FMT could be a great alternative for
22
Discussion and conclusion
The bacteria that inhabit our intestines are responsible of many current diseases,
as well as our health. Studies have shown that dysbiosis of gut microbiota occurs in
PCOS: alpha diversity decreases, and the ratio or abundance of some bacteria related to
controls.
with PCOS, leaving aside studies with animal models, which other magazines have not
done. Moreover, we summarized not only the alterations of the gut microbiota in humans
with PCOS but also the correlations between the gut microbiota and different PCOS
features.
At this time there is no cure for PCOS. However, it has been shown from this
review that with proper treatment, many of the symptoms could be controlled. Having
into account that every PCOS phenotype have different features and symptoms, more
studies are required to find out the association between the causes of dysbiosis of the gut
Besides, the heterogenicity of the pathogenesis makes crucial the need for more
studies to better understand the mechanisms and association between PCOS and gut
23
Taking everything into consideration, we can reach an agreement and say that diet
modulation is not only an excellent, but also a low-risk strategy to help change the
microbiome. As Hippocrates said once “Let food be the medicine, and let medicine be
the food”. So, in light of this, it would be a must for females with PCOS to focus on the
microbiota and live a healthy lifestyle, including an anti-inflammatory diet and probiotics.
Additionally, the data obtained from recent studies show us the relationship
between androgens in PCOS and COVID-19. Hence, knowing about the possible crucial
about the possible relation between PCOS, gut microbiota and the severity of COVID-
24
REFERENCES
1. Guo J, Shao J, Yang Y, Niu X, Liao J, Zhao Q, et al. Gut Microbiota in Patients with
2. Tremellen K, Pearce K. Dysbiosis of Gut Microbiota (DOGMA) - A novel theory for the
3. Rizk MG, Thackray VG. Intersection of polycystic ovary syndrome and the gut
Metab. 1998;83(10):3558-62.
5. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future
6. Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM, Cusack S, et al. Gut
microbiota composition correlates with diet and health in the elderly. Nature. 2012
Aug;488(7410):178-84.
803.
9. Liu H, Hu C, Zhang X, Jia W. Role of gut microbiota, bile acids and their cross-talk in
the effects of bariatric surgery on obesity and type 2 diabetes. J Diabetes Investig. 2018
Jan;9(1):13-20.
25
Physiological and clinical implications. Maturitas. 2017 Sep;103:45-53.
11. Wang L, Zhou J, Gober HJ, Leung WT, Huang Z, Pan X, Li C, Zhang N, Wang L.
Alterations in the intestinal microbiome associated with PCOS affect the clinical
12. Akgül S, Sur Ü, Düzçeker Y, Balcı A, Kanbur N, Bozdağ G et al. Bisphenol A and
2019,35:1084–1087.
14. Merlo E, Silva IV, Cardoso RC, Graceli JB. The obesogen tributyltin induces features of
polycystic ovary syndrome (PCOS): a review. J Toxicol Environ Health Part B Crit Rev
2018;21(3):181-206.
15. Barber TM, Kyrou I, Randeva HS, Weickert MO. Mechanisms of insulin resistance at the
16. Jobira B, Frank DN, Pyle L, Silveira LJ, Kelsey MM, Garcia-Reyes Y, et al. Obese
17. Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, et al. Dysbiosis of gut microbiota
associated with clinical parameters in polycystic ovary syndrome. Front Microbiol. 2017
Feb;8:324.
18. Liang Z, Di N, Li L, Yang D. Gut microbiota alterations reveal potential gut–brain axis
26
19. Insulin Resistance & Prediabetes | NIDDK [Internet]. National Institute of Diabetes and
Digestive and Kidney Diseases. 2021 [cited 23 March 2021]. Available from:
https://www.niddk.nih.gov/health-information/diabetes/overview/what-
isdiabetes/prediabetes-insulin-resistance#prediabetes .
20. He F, Li Y. The gut microbial composition in polycystic ovary syndrome with insulin
22. He F-F, Li Y-M. Role of gut microbiota in the development of insulin resistance and the
Jun;13:73.
25. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS.
525.
particles in adolescents and young women with PCOS provide insights into their
27
27. Saito K, Matsuzaki T, Iwasa T, Miyado M, Saito H, Hasegawa T, et al. Steroidogenic
28. Crommen S, Simon MC. Microbial Regulation of Glucose Metabolism and Insulin
29. Torres PJ, Siakowska M, Banaszewska B, Pawelczyk L, Duleba AJ, Kelley ST, et al. Gut
30. Silva MSB, Desroziers E, Hessler S, Prescott M, Coyle C, Herbison AE, Campbell RE.
31. Steegers-Theunissen RPM, Wiegel RE, Jansen PW, Laven JSE, Sinclair KD. Polycystic
32. Thannickal A, Brutocao C, Alsawas M, Morrow A, Zaiem F, Murad MH, et al. Eating,
sleeping and sexual function disorders in women with polycystic ovary syndrome
Apr;92(4):338-349.
33. Jeanes YM, Reeves S, Gibson EL, Piggott C, May VA, Hart KH. Binge eating behaviours
and food cravings in women with Polycystic Ovary Syndrome. Appetite. 2017
Feb;109:24-32.
34. Lam YY, Maguire S, Palacios T, Caterson ID. Are the Gut Bacteria Telling Us to Eat or
Not to Eat? Reviewing the Role of Gut Microbiota in the Etiology, Disease Progression
28
35. Wieland A, Frank DN, Harnke B, Bambha K. Systematic review: microbial dysbiosis and
Non-alcoholic fatty liver disease is associated with insulin resistance and lipid
accumulation product in women with polycystic ovary syndrome. Hum Reprod. 2016
Jun;31(6):1347–53.
37. Carreau AM, Pyle L, Garcia-Reyes Y, Rahat H, Vigers T, Jensen T, et al. Clinical
prediction score of nonalcoholic fatty liver disease in adolescent girls with polycystic
38. Jobira B, Frank DN, Silveira LJ, Pyle L, Kelsey MM, Garcia-Reyes Y, et al. Hepatic
39. Del Chierico F, Nobili V, Vernocchi P, Russo A, De Stefanis C, Gnani D, et al. Gut
microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients
464.
40. Baranova A, Tran TP, Afendy A, Wang L, Shamsaddini A, Mehta R, et al. Molecular
signature of adipose tissue in patients with both non-alcoholic fatty liverdisease (NAFLD)
42. Singeap A-M, Stanciu C, Huiban L, Muzica CM, Cuciureanu T, Girleanu I, et al.
29
43. Meng G, Zhang B, Yu F, Li C, Zhang Q, Liu L, et al. Soft drinks consumption is
44. Vancells P, Viñas E, Sacanella E. Overview of non-alcoholic fatty liver disease (NAFLD)
and the role of sugary food consumption and other dietary components in its development.
and Gut Microbiota in Obesity and Polycystic Ovary Syndrome. Front Endocrinol
46. Dhayat NA, Marti N, Kollmann Z, Troendle A, Bally L, Escher G, et al. Urinary steroid
Oct;13(10):e0203903.
47. Zhou W, Hong Y, Yin A, Liu S, Chen M, Lv X, et al. Non-invasive urinary metabolomics
reveals metabolic profiling of polycystic ovary syndrome and its subtypes. J Pharm
48. Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
309.
49. Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe COVID-
19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Critical
30
50. Morgante G, Troìa L, De Leo V. Coronavirus Disease 2019 (SARS-CoV-2) and
polycystic ovarian disease: Is there a higher risk for these women? J Steroid Biochem
51. Barber TM. COVID-19 and diabetes mellitus: implications for prognosis and clinical
52. Fontana L, Partridge L. Promoting health and longevity through diet: From model
with polycystic ovary syndrome: A review study. Diabetes Metab Syndr. 2017
Nov;11(1):429–432.
56. Chien Y-J, Chang C-Y, Wu M-Y, Chen C-H, Horng Y-S, Wu H-C. Effects of Curcumin
Review with Meta-Analysis and Trial Sequential Analysis. Nutrients. 2021 Feb;
13(2):684.
57. Tehrani H.G., Allahdadian M., Zarre F., Ranjbar H., Allahdadian F. Effect of green tea
obese women suffering from polycystic ovarian syndrome: A clinical trial. J Educ Health
31
58. Haudum C, Lindheim L, Ascani A, Trummer C, Horvath A, Münzker J, et al. Impact of
60. Zhang J, Sun Z, Jiang S, Bai X, Ma C, Peng Q, et al. Probiotic Bifidobacterium lactis V9
Regulates the Secretion of Sex Hormones in Polycystic Ovary Syndrome Patients through
profiles, and biomarkers of inflammation and oxidative stress in women with polycystic
32
Appendix 1
Correlation analysis of gut microbiota, fecal metabolites and serum sex hormones in obese
PCOS group. (A) Correlation heatmap between seven important differential fecal metabolites
and the top 30 genera in abundance. (B) Correlation heatmap between serum sex hormones and
the top 30 genera in abundance. (C) Correlation heatmap between serum sex hormones and
seven important differential fecal metabolites. Different colors represent correlation level; *p <
0.05; **p < 0.01, ***p < 0.001. (D) Correlation map among gut microbiota, fecal metabolites
and serum sex hormones. The red line represents a significant positive correlation, while the
green line represents a significant negative correlation; the up arrow represents an increase in
abundance, while the down arrow represents a decrease in abundance; one, two and three arrows
represents p > 0.05, p < 0.01, and p < 0.001, respectively.
33
Figure 1
34
Figure 2
Figure 2. Psychological distress and its associated eating disorders could lead to the epigenetic
35
Figure 3
36